Mutation in the MICOS subunit gene APOO (MIC26) associated with an X-linked recessive mitochondrial myopathy, lactic acidosis, cognitive impairment and autistic features
| Autor: | Alexander J. Whitworth, Julien Prudent, Enrico Baruffini, Anna Yeates, Daniel Almeida do Valle, Alan J. Robinson, Erika Fernandez-Vizarra, Michele Brischigliaro, Aurelio Reyes, Mara Lúcia Schmitz Ferreira Santos, Ricardo L.R. Souza, Mark H. Johnson, Massimo Zeviani, Bruno Augusto Telles, Andrea Degiorgi, Cristiane Benincá, Vanessa Zanette |
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| Přispěvatelé: | Prudent, Julien [0000-0003-3821-6088], Whitworth, Alex [0000-0002-1154-6629], Apollo - University of Cambridge Repository |
| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Saccharomyces cerevisiae Proteins clinical genetics genetics metabolic disorders neuromuscular disease Acidosis Lactic Animals Apolipoproteins Autistic Disorder Cognitive Dysfunction Drosophila melanogaster Fibroblasts Genetic Diseases X-Linked Humans Membrane Proteins Mitochondrial Membranes Mitochondrial Myopathies Mitochondrial Proteins Protein Binding Saccharomyces cerevisiae Biology Mitochondrion medicine.disease_cause 03 medical and health sciences 0302 clinical medicine Mitochondrial myopathy Genetics medicine Inner mitochondrial membrane Genetics (clinical) X-linked recessive inheritance Exome sequencing Mutation Lactic X-Linked medicine.disease biology.organism_classification 030104 developmental biology Genetic Diseases Lactic acidosis Acidosis 030217 neurology & neurosurgery |
| Zdroj: | Journal of Medical Genetics. 58:155-167 |
| ISSN: | 1468-6244 0022-2593 |
| DOI: | 10.1136/jmedgenet-2020-106861 |
| Popis: | BackgroundMitochondria provide ATP through the process of oxidative phosphorylation, physically located in the inner mitochondrial membrane (IMM). The mitochondrial contact site and organising system (MICOS) complex is known as the ‘mitoskeleton’ due to its role in maintaining IMM architecture. APOO encodes MIC26, a component of MICOS, whose exact function in its maintenance or assembly has still not been completely elucidated.MethodsWe have studied a family in which the most affected subject presented progressive developmental delay, lactic acidosis, muscle weakness, hypotonia, weight loss, gastrointestinal and body temperature dysautonomia, repetitive infections, cognitive impairment and autistic behaviour. Other family members showed variable phenotype presentation. Whole exome sequencing was used to screen for pathological variants. Patient-derived skin fibroblasts were used to confirm the pathogenicity of the variant found in APOO. Knockout models in Drosophila melanogaster and Saccharomyces cerevisiae were employed to validate MIC26 involvement in MICOS assembly and mitochondrial function.ResultsA likely pathogenic c.350T>C transition was found in APOO predicting an I117T substitution in MIC26. The mutation caused impaired processing of the protein during import and faulty insertion into the IMM. This was associated with altered MICOS assembly and cristae junction disruption. The corresponding mutation in MIC26 or complete loss was associated with mitochondrial structural and functional deficiencies in yeast and D. melanogaster models.ConclusionThis is the first case of pathogenic mutation in APOO, causing altered MICOS assembly and neuromuscular impairment. MIC26 is involved in the assembly or stability of MICOS in humans, yeast and flies. |
| Databáze: | OpenAIRE |
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